HUP0303600A2 - Novel use of a peptide class of compound for treating non neuropathic inflammatory pain - Google Patents

Abstract

The invention relates to the use of the compounds of general formula (I) for the treatment of acute and chronic pain of various types and symptoms, especially non-neuropathic inflammatory pain. The pain to be treated can be, for example, chronic inflammatory pain, rheumatic arthritis pain and/or secondary inflammatory osteoarthritis pain. The compounds have an antinociceptive profile and are distinct from conventional analgesics such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs) and can be used as specific analgesics. In the general formula (I), R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic compound, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or substituted with at least one electron withdrawing or donating group; R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic compound, lower cycloalkyl, lower cycloalkyllower alkyl, all of which are unsubstituted or have at least one electron withdrawing or donating group substituted; and R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, lower alkyl, aryl, heterocyclic compound, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y , where R2 and R3 can be unsubstituted or substituted with at least one electron-withdrawing or donating group; HE

Description

substituted;

Novel application of peptide compounds for the treatment of non-neuropathic inflammatory pain

KOZzf r ' - . : j í- । ljAí'xjv

The present invention is directed to a novel use of compounds belonging to a given peptide class for the treatment of various types of pain presenting acute as well as chronic symptoms, particularly non-neuropathic inflammatory pain.

Certain peptides are known to exhibit activity in the central nervous system (CNS) and to be useful in the treatment of epilepsy and other CNS disorders. These peptides, which are described in the literature [U.S. Patent Application No. 5,378,729], have the general formula (I), where

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or substituted with at least one electron withdrawing or donating group;

R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic compound, lower cycloalkyl, lower cycloalkyl lower alkyl, all of which are unsubstituted or substituted.

-2- ·..*· :··.*···* substituted or substituted with at least one electron withdrawing or donating group; and

R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic compound, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y, where R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing or donating group;

Z is O, S, S(O)2, NR4, PR4 or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halogen, heterocyclic compound, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with at least one electron withdrawing or donating group; provided that Y is halogen, Z is a bond, or

The collective meaning of ZY is as follows: NR4NR5R7, NR4OR5, ONR4R7, OPR4R7, PR4OR5, SNR4R7, NR4SR7, SPR4R5 or PR4SR7, NR4PR5R6 or PR4NR5R7, NR4C-R5, SCR ₅ , NR4C-OR5, SC-OR5;

II II II II

0000

R ₄ , Rs and R 6 independently represent hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, where R 4 , Rs and R 7 may be non-

-3- ··;· substituted or substituted with at least one electron withdrawing or donating group; and

R7 is R8 or COOR8 or COR8;

R s is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing or donating group; and n is 1-4; and a is 1-3.

U.S. Patent Application No. 5,773,475 further discloses compounds useful in the treatment of CNS disorders. These compounds are N-benzyl-2-amino-3-methoxypropionamides, the structure of which can be described by the general formula (II), where

Ar is aryl which is unsubstituted or substituted by halogen;

R3 is lower alkoxy; and

R1 is lower alkyl, of which methyl is particularly preferred.

The patent applications cited herein are incorporated by reference. However, none of the above patent applications describe these compounds as specific analgesics for acute and chronic pain, especially as analgesics for rheumatoid inflammatory pain. In particular, the antinociceptive profiles and properties of these compounds are not disclosed.

Accordingly, the present invention relates to a novel use of compounds of formula (I) and (II) which exhibit antinociceptive properties in the treatment of various types of acute and chronic pain.

-4In the treatment of pain with chronic symptoms, especially non-neuropathic inflammatory pain.

More specifically, the present invention relates to the use of said compounds of formula (I) and (II) and/or to the preparation of pharmaceutical compositions thereof, which are suitable for the treatment of pain presenting various types of acute and chronic symptoms, in particular non-neuropathic inflammatory pain. This includes chronic inflammatory pain, such as pain in rheumatoid arthritis and/or secondary inflammatory osteoarthritis.

The structure of the compound of the present invention can be described by the general formula (I), where

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or substituted with at least one electron withdrawing or donating group;

R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic compound, lower cycloalkyl, lower cycloalkyl lower alkyl, all of which are unsubstituted or substituted with at least one electron withdrawing or donating group; and

-5R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic compound, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y, where R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing or donating group;

Z is O, S, S(O) ₂ , NR 4 , PR 4 or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halogen, heterocyclic compound, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with at least one electron withdrawing or donating group; provided that Y is halogen, Z is a bond, or

The collective meaning of ZY is as follows: NR4NR5R7, NR4OR5, ONR4R7, OPR4R7, PR4OR5, SNR4R7, NR4SR7, SPR4R5 or PR4SR7, NR4PR5R6 or PR4NR5R7, NR4C-R5, SCR ₅ , NR4C-OR5, SC-OR5;

OOOO

R4, Rs and R0 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, where R4, Rs and R0 may be unsubstituted or substituted with at least one electron withdrawing or donating group; and

_-6R7 is Re> or COOR8 or COR8;

R s is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing or donating group; and n is 1-4; and a is 1-3.

The structure of a further compound of the present invention can be described by the general formula (II), where

Ar is aryl which is unsubstituted or substituted by halogen; R3 is lower alkoxy; and R1 is lower alkyl, of which methyl is particularly preferred.

The present invention is also directed to pharmaceutical compositions comprising a compound of formula (I) and/or (II), which pharmaceutical compositions are useful for the treatment of rheumatic inflammatory pain.

As indicated above, the compounds of formula (I) are useful in the treatment of pain, particularly non-neuropathic inflammatory pain. Such types of pain include chronic inflammatory pain, such as rheumatoid arthritis pain and/or secondary inflammatory osteoarthritic pain. They are antinociceptive in nature.

These compounds are described in the literature [U.S. Patent Application No. 5,378,729, which is incorporated herein by reference in its entirety].

As defined herein, alkyl groups are those that contain, alone or in combination with other groups, 1-6 carbon atoms.

-7 When used with carboxylic acid groups, they are low carbon and straight or branched chain. These include the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl and the like.

Examples of aryl lower alkyl groups include benzyl, phenethyl, phenpropyl, phenisopropyl, phenbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

The term aryl, when used alone or in combination, refers to aromatic groups containing 6 to 18 ring carbon atoms and a total of 25 carbon atoms, which are classified as polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and fused rings. As used herein, polynuclear aromatic compounds include bicyclic and tricyclic fused aromatic ring systems containing 10 to 18 ring carbon atoms and a total of 25 carbon atoms. Aryl groups include phenyl and polynuclear aromatics such as naphthyl, anthracenyl, phenanthrenyl, azulenyl, and the like. Aryl groups also include, for example, ferrocenyl.

Lower alkenyl refers to an alkenyl group containing 2 to 6 carbon atoms and at least one double bond. These groups may be straight or branched chain and in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl; pentadienyl, such as 1, 3 or 2,4-pentadienyl, and the like.

-8Lower alkynyl is an alkynyl group containing 2 to 6 carbon atoms and can be straight or branched chain. These include the following groups: ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl; 3-hexynyl and the like.

The term lower cycloalkyl is used alone or in combination to refer to cycloalkyl groups having the following properties: having 3 to 8 ring carbon atoms and up to a total of 25 carbon atoms. Cycloalkyl groups may be monocyclic, bicyclic, tricyclic or polycyclic and fused rings. Cycloalkyl may be fully or partially saturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, phenyl, pinenyl, adamantyl and the like. Cycloalkyls may be in the cis or trans form. Furthermore, in bridged bicyclic systems, the substituents may be in either the endo or exo positions.

The term electron-withdrawing or electron-donating refers to the ability of a substituent to accept or donate an electron relative to hydrogen when the hydrogen atom occupies the same position in the molecule. These terms are well known in the art [Advanced Organic Chemistry, J. March, John Wiley and Sons, New York, NY, 16-18 (1985), which is incorporated herein by reference in its entirety]. Electron-withdrawing groups include: halogens, including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, lower alkenyl, lower

-9-alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl, carbalkoxy and the like. Electron donating groups include hydroxy, lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl and the like, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide(lower alkyldithio) and the like. It will be apparent to those skilled in the art that some of the above-mentioned substituents may be electron donating or electron withdrawing depending on the chemical circumstances. Furthermore, the present invention also encompasses any combination of the substituents defined above.

The term halogen refers to fluoro, chloro, bromo, iodo and the like.

The term acyl encompasses lower alkanoyls.

As used herein, heterocyclic substituents contain at least one sulfur, nitrogen, or oxygen atom, but may contain one or more of such atoms in the ring. Heterocyclic substituents contemplated in the present invention include heteroaromatic and saturated, and particularly include partially saturated heterocyclic compounds. These heterocyclic compounds may be monocyclic, bicyclic, tricyclic, or polycyclic and may be fused rings. They may contain up to 18 ring carbon atoms and up to 25 total carbon atoms. The heterocyclic compounds

-ίο, the so-called benzohetrocyclic forms are also considered. Representatives of the heterocyclic forms are the following: furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, nitrogen-containing heterocyclic N-oxides, such as the nitric oxides of pyridyl, pyrazinyl and pyrimidinyl, and the like. Preferred heterocyclic forms are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridinyl, pyrazinyl, imidazolyl, pyrimidinyl or pyridazinyl. Preferred heterocyclic compounds are 5- or 6-membered. Particularly preferred heterocyclics are furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl or pyridazinyl. Furyl and pyridyl are most preferred.

Preferred compounds of the present invention include those in which n is 1, but di-, tri- and tetrapeptides are also contemplated within the claims of the present invention.

Preferred R is aryl lower alkyl, especially benzyl, where the phenyl ring is unsubstituted or has an electron donating or electron withdrawing group such as halogen (e.g. F).

The preferred R 1 is H or lower alkyl. The most preferred R 1 group is methyl.

The most preferred electron-donating and electron-withdrawing substituents are: halogen, nitro, alkanoyl, formyl, arylalkanoyl

-11 «4 noyl, aryl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio and alkyldithio. The term sulfide includes mercapto, mercapto alkyl and alkyldithio, while the term disulfide refers to alkyldithio. These preferred substituents may be replaced by any of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 , R 7 or R 8 as defined herein.

ZY groups are representatives of R2 and R3, which include: hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy, such as thiophenoxy; amino; alkylamino, such as methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino, such as dimethylamino; trialkyl ammonium salt, hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxyhydrazino, aralkoxycarbonylhydrazino, aryloxycarbonylhydrazino, hydroxylamino, such as N-hydroxylamino (-NH-OH), lower alkoxyamino [(NHORiS), where R1S is lower alkyl], N-lower alkylhydroxylamino [(NRiS)OH, where R1S is lower alkyl], N-lower alkyl-O-lower alkylhydroxyamino, i.e. [N(RiS)ORi9, where R1S and R19 are independently lower alkyl], and o-hydroxylamino (-O-NH2); alkylamido, such as

-12acetamido; trifluoroacetamido; lower alkoxyamino, (e.g. NH(OCH3); and heterocyclic-amino, such as pyrazoylamino.

The most preferred heterocyclic groups for R2 and R3 are monocyclic heterocyclic groups having the structure of formula (III) or those which are partially or fully saturated when n is 0 or 1; and

Rso represents H or an electron withdrawing or donating group;

A, Z, L and J are independently CH or a heteroatom selected from the group consisting of N, O, S; and

G is CH, or a heteroatom selected from the group consisting of N, O, S;

but wherein O, G is CH, or a heteroatom selected from the group consisting of NH, O and S, with the proviso that at most two of A, E, L, J and G are heteroatoms.

When n is 0, the above heteroaromatic group is a five-membered ring, while when n is 1, the heterocyclic group is a six-membered monocyclic heterocyclic group. Preferred heterocyclic groups are monocyclic forms of the above-mentioned heterocyclic compounds.

If the ring as described above contains a nitrogen ring atom, the N-oxide forms are also within the scope of the present invention.

If R2 or R3 are independently a heterocyclic form of the above formula, they may be attached to the main chain via a ring carbon atom. If n is O, R2 or R3, they may be attached to the main chain via a nitrogen ring atom.

-13 Further preferred R ₂ and R 3 groups are hydrogen, aryl, such as phenyl, arylalkyl, such as benzyl, and alkyl.

It is to be understood that the preferred R ₂ and R 3 groups are either unsubstituted or substituted with electron donating or electron withdrawing groups. The preferred R ₂ and R 3 are independently hydrogen, lower alkyl, which are either unsubstituted or substituted with electron withdrawing or electron donating groups, examples of the latter being lower alkoxy (e.g. methoxy, ethoxy and the like), N-hydroxylamino, N-lower alkylhydroxyamino, N-lower alkyl O-lower alkyl and alkylhydroxyamino.

Even more preferably, R ₂ and R ₃ are hydrogen. It is preferred that n is one.

It is preferred that _R2 is hydrogen, while R3 is hydrogen, an alkyl group which is unsubstituted or substituted with at least one electron donating or electron withdrawing group, or ZY. In this preferred embodiment, it is more preferred that R3 is hydrogen, an alkyl group such as methyl which is unsubstituted or substituted with at least one electron donating group, or NR4ORs or _ONR4R7 , where R4, Rs and R7 are independently hydrogen or lower alkyl. It is preferred that the electron donating group is lower alkoxy, and in particular methoxy or ethoxy.

It is also preferred that R aryl is lower alkyl. Most preferred R aryl is phenyl. Most preferred R group is benzyl. In one preferred embodiment, the aryl group may be unsubstituted or electron donating.

-14or substituted with an electron withdrawing group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halogen, especially fluoro.

Preferred R 1 is lower alkyl, especially methyl.

In the compounds of formula (I), it is preferred that n is 1; R2 is hydrogen; R3 is hydrogen, an alkyl group, especially methyl, substituted with an electron donating or electron withdrawing group or ZY; R is aryl, aryl lower alkyl such as benzyl, wherein the aryl group is unsubstituted or substituted and R1 is lower alkyl. In this embodiment, it is preferred that R3 is hydrogen, an alkyl group, especially methyl, substituted with an electron donating group, such as lower alkoxy, (e.g. methoxy, ethoxy and the like), NR4OR5 or ONR4R7, wherein these groups are as defined above.

Among the compounds used, the most preferred are those of general formula (II), where

Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one electron-donating or electron-withdrawing group,

R1 is lower alkyl; and

R3 is as defined above, but in particular hydrogen, lower alkyl which is unsubstituted or substituted with at least one electron donating or electron withdrawing group or ZY. More preferably, R3 in this case is

-15 In embodiment, hydrogen is an alkyl group which is unsubstituted or substituted with electron donating groups, NR4OR5 or ONR4R7. Most preferably, R3 is also CH2-Q, where Q is lower alkoxy, NR4OR5 or ONR4R7, where R4 is hydrogen or alkyl containing 1-3 carbon atoms, R5 is hydrogen or alkyl containing 1-3 carbon atoms, and R7 is hydrogen or alkyl containing 1-3 carbon atoms.

The preferred R 1 is CH 3 . The most preferred R 3 is methoxy. The most preferred aryl is phenyl. The most preferred compounds include: (R)-2-acetamido-N-benzyl-3-methoxypropionamide, O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;

O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;

N-acetyl-D-phenylglycine benzylamide;

D-1,2-(N,O-Dimethylhydroxylamino)-2-acetamidoacetic acid benzylamide;

D-1,2-(O-methylhydroxylamino)-2-acetamidoacetic acid benzylamide.

It is to be understood that various combinations and permutations of the Markush groups Ri, R2, R3, R and n described herein are also within the scope of the present invention. Furthermore, the present invention also encompasses compounds and compositions comprising one or more of the Markush groups Ri, R2, R3, R and n and various combinations thereof. Thus, for example, the present invention contemplates that R1 may be one or more of the substituents listed herein, in combination with any or all of the substituents R2, R3 and R, with the appropriate values of n.

-16The compounds used in the practice of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The configuration of each asymmetric carbon atom may be either the D or L form. It is well known to those skilled in the art that the configuration around the chiral carbon atom may be either R or S according to the Cahn-Prelog-Ingold nomenclature system. All of the different configurations around each asymmetric carbon atom may occur, including different enantiomers and diastereomers, as well as racemate mixtures and mixtures of enantiomers; both diastereomers are contemplated in the present invention.

The asymmetry in the backbone occurs at the carbon atom to which the R2 and R3 groups are attached. When n is 1, the structure of the compounds of the present invention can be described by the general formula IV, where R, Ri, R2, R3, R4, Rs, Re, Z and Y are as defined above.

As used herein, the term configuration refers to the carbon atom to which R2 and R3 are attached, even if the molecule contains a chiral center. Therefore, when we refer to a particular configuration, such as D or L, we should understand that D or L is the stereoisomer of the atom to which R2 and R3 are attached. However, it also encompasses all possible enantiomers and diastereomers or chiral centers, if any.

The compounds of the present invention also include all optical isomers, i.e., the compounds of the present invention are either L-stereoisomers or D-stereoisomers (at the carbon atom where

-17 to which R2 and R3 are attached). These stereoisomers can be found as a mixture of L and D forms, for example as a racemic mixture. The D stereoisomer is preferred.

Depending on the substituents, the compounds of the present invention may also form addition salts. All such forms, including mixtures of stereoisomeric forms, are contemplated within the scope of the present invention.

The preparation of the compounds used is described in the literature [U.S. Patent Applications Nos. 5,378,729 and 5,773,475, which are incorporated herein by reference in their entirety],

The compounds of the present invention, such as the compounds of formula (I), are useful or may be used in salt forms, depending on the basic nature of the free amino group. Thus, the compounds of formula (I) form salts with a wide variety of acids, such as inorganic and organic acids, including pharmaceutically acceptable acids.

Salts with therapeutically acceptable acids are of course useful in preparing formulations where water solubility is most advantageous. These pharmaceutically acceptable salts may also have therapeutic effects. These include: salts of inorganic acids such as hydrochloric acid, hydroiodide, hydrobromide, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts of organic acids such as tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, perchloric acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acids (e.g., p-toluenesulfonic acids, benzenesulfonic acid), phosphoric acid, malonic acid and the like.

According to the present invention, it is preferred to use the compound in a pharmaceutically effective amount. The present invention

The dosage of the therapeutic agent may be determined by the practitioner, taking into account the form of administration and the particular compound, and the amount thereof may vary according to the age of the patient being treated, the state of his disease, etc. Treatment is generally initiated with small doses, less than the optimal dose of the compound, and then gradually increased doses are administered in small increments until the desired effect is achieved. It is generally observed that the amount of active agent required for an orally administered composition is greater than that required for parenteral administration to achieve the same effect.

The compounds are comparable to the same and other therapeutic agents and the magnitude of their dose levels.

In one preferred embodiment, the compound is administered in a range of about 1 to 100 mg/kg body weight/day. This dosage range may be adjusted by the physician to achieve the optimal therapeutic response. For example, multiple divided doses may be administered daily, or the dosage may be reduced proportionally as the therapeutic situation requires.

The compounds of formula (I) may conveniently be administered by the following routes: orally, intravenously (where the compound is water soluble), intramuscularly or subcutaneously. The compounds of formula (I) may be administered orally, for example, with an inert diluent or an edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or directly incorporated into the diet. For oral therapeutic use, the active compound of formula (1) may be formulated with a binder and administered in the form of tablets, buccal tablets, pills, capsules, elixirs, suspensions, syrups, wafers, and the like.

-19 can be used. Such compositions and preparations should contain at least 1% of the active compound of formula (I). The percentage of the composition and preparation can of course vary and can conveniently be from about 5 to about 80% by weight. The amount of active compound of formula (I) in such therapeutically useful compositions will provide the appropriate dosages. Preferred compositions or preparations according to the present invention contain from 10 mg to 6 g of active compound of formula (I).

Tablets, pills, troches, capsules and the like may also contain the following materials: a binder such as gum tragacanth, acacia, corn starch or gelatin; a binder such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin, and a flavoring agent such as peppermint, oil of wintergreen or cherry flavor may be added. When the dosage unit form is a capsule, it may contain a liquid carrier in addition to the materials listed above.

Many other materials may be present as coatings or other forms that modify the physical form of the dosage unit. For example, tablets, pellets, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, propylparabens as a preservative, and cherry or orange flavors as a colorant and flavoring. Of course, any material used in any dosage unit form must be pharmaceutically pure and substantially nontoxic in the amounts employed. Furthermore, the active compound

-20Compound can also be incorporated into a sustained release formulation and packaging. For example, we consider sustained release dosage forms in which the active ingredient is bound to an ion exchange resin, which can be optionally coated with a diffusion barrier, thereby providing for modification of the release capacity of the resin.

The active compound may be administered parenterally or intraperitoneally. Dispersions may also be prepared in glycerin, liquids, polyethylene glycols and mixtures thereof, and oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions (where the compound is water-soluble) or dispersions, and sterile powders when the sterile injectable solutions or dispersions are preparations prepared immediately before use. In all cases, the form should be sterile and fluid to the extent that easy injectability is assured. It should remain stable during manufacture and storage and should be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier solution or dispersion may be, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol and liquid propylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Adequate fluidity may be maintained, for example, by a coating such as lecithin, while in the case of dispersions, by maintaining the desired particle size and by the use of a surfactant. Inhibition of the action of microorganisms may be ensured by various antibacterial and antifungal agents, such as

-21 for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it is advantageous to include isotonic agents such as sugars or sodium chloride. Prolonged absorption of the injectable composition can be achieved by the use of compositions delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the desired amount of the active compound in a suitable solvent with various additional ingredients as required, followed by sterile filtration. Dispersions may generally be prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the necessary additional ingredients as listed above. In the case of powders which are formulated into sterile injectable solutions, the preferred preparation methods are vacuum drying, freeze drying and, optionally, sterile filtration of the necessary additional ingredients.

As used herein, the term pharmaceutically acceptable carrier includes any and all of the following: solvents, dispersion media, coatings, antibacterial and antifungal agents, agents to delay isotonicity and absorption of the pharmaceutically active agents, as are known in the art. With the proviso that any conventional medium or agent is compatible with the active agent and is useful in the therapeutic composition. Additional active ingredients may also be incorporated into the compositions.

Particularly preferred are parenteral formulations which are in unit dosage form or are easy to use and where the dosage is uniform. As used herein, the dosage

The term "unit forms" refers to physically discrete units suitable for a single dosage form for the mammal to be treated; each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, taking into account the necessary pharmaceutical carrier. The specificity of the novel dosage unit forms of the present invention is independently influenced by: (a) the unique characteristics of the active ingredient for the particular therapeutic effect to be achieved, and (b) the inherent limitations of the formulation of the active ingredient, such as the active ingredient for the treatment of disease in a living subject suffering from a disease in which physical health is impaired, as disclosed in detail herein.

The essential active ingredient is formulated in an effective amount for convenient and effective administration with a suitable pharmaceutically acceptable carrier in a dosage unit form as described above. For example, a unit dosage form may contain from about 10 mg to about 6 g of the essential active compound. In gold, the active compound is generally present in about 1 to about 750 mg/ml of the carrier. In the case of compositions containing additional active ingredients, the dosages are determined in accordance with the usual dosage and route of administration of the ingredient in question.

As used herein, the terms patient or subject refer to warm-blooded animals, and preferably mammals, such as cats, dogs, horses, cows, pigs, rats, and primates, including humans. The preferred patient is a human.

The term treatment refers to either alleviating the pain associated with a disease or condition or alleviating the disease or condition of a patient.

The compound of the present invention is useful in the treatment of chronic pain. As used herein, the term chronic pain refers to pain that persists for a prolonged period of time, for example, more than 3-6 months, although the characteristic symptoms described herein may occur earlier or later than this period. Autonomic symptoms develop, such as fatigue, sleep problems, decreased appetite, taste loss, weight loss, decreased libido, and constipation.

The compounds of the present invention are particularly suitable for the treatment of acute and chronic types of pain, with particular reference to non-neuropathic inflammatory pain. This includes chronic inflammatory pain, such as rheumatoid arthritis pain, and/or secondary inflammatory osteoarthritis pain.

The compounds of the present invention are administered to patients experiencing the above-mentioned pain conditions in an amount sufficient to provide analgesia. These amounts are the same as the therapeutically effective amounts described above.

The following working examples demonstrate antinociceptive properties in well-defined acute and chronic animal models.

The substance used is called SPM 927, which is synonymous with Harkoseride. According to standard chemical nomenclature, it is (R)-2-acetamide-N-benzyl-3-methoxypropionamide.

-24« · · > ·'·>♦ ·

Example 1

Formalin test method in rats

Prolonged inflammatory pain:

Significant and dose-dependent effects of SPM 927 can be demonstrated in the late phase of the rat formalin test. The formalin test is an example of a chemically induced ionized pain model in which biphasic changes in nociceptive behavior are determined and spinal/supraspinal plasticity of nociception is investigated with regard to the molecular basis of neuropathic pain, in the second (late) phase of the test, during which most clinically used neuropathic analgesics are active. These features make the formalin test suitable as a model for the study of persistent clinical pain.

The antinociceptive properties of the compound were tested using a weighted behavioral assessment procedure. In freely moving animals, the left hind paws were observed, where scores ranging from 0 to 3 were obtained before and 10, 20, 30 and 40 minutes after injection of 0.05 ml of sterile 2.5% formalin (subcutaneously on the dorsal surface of the paw). SPM 927, administered ip, immediately before formalin injection, dose-dependently reduced formalin-induced tonic inflammatory nociceptive behavior, as can be seen from the table (weighted pain score ± SEM, n = 11-12 per group).

Table -251

Weighted pain value, formalin test, rat

Time elapsed after formalin and SPM 927 injection Dose mg/kg Number of animals Baseline 10 minutes 20 minutes 30 minutes 40 minutes 0 11 0.00±0.00 0.30±0.16 0.93±0.21 1.84±0.19 2.10±0.24 5 12 0.01±0.01 0.31±0.11 0.78+0.23 1.47±0.20 1.46±0.19* 10 11 0.00+0.00 0.42±0.17 0.33±0.16* 1.02+0.27* 1.05+0.19* 20 12 0.00±0.00 0.48±0.18 0.57±0.14 0.78±0.18* 1.02±0.24* 40 12 0.00±0.00 0.12±0.05 0.10±0.04* 0.09±0.06* 0.12±0.06*

= significant difference compared to vehicle (ANOVA, corrected for multiple comparisons, p < 0.05).

Example 2

Chronic compression injury (CCI, Benneti model)

The efficacy of SPM 927 in reducing spontaneous chronic pain, mechanical allodynia and thermal hypersensitivity was investigated using the chronic injury (CCI) model of peripheral neuropathy, which is one of the best characterized in vivo animal models for the study of chronic pain, as pain is a consequence of peripheral nerve injury. In this model, loose fibrils are placed around the sciatic nerve, which manifests as axonal swelling and partial deafferentation, resulting in significant but not complete axonal loss in the distal part of the peripheral nerve. One of the prominent behaviors following sciatic nerve ligation is the appearance of hindpaw guarding, which is thought to be a sign of spontaneous chronic pain. Supporting this idea are the

-26a are derived from articles reporting increased spontaneous neuronal firing in the spinothalamic tract and an apparent lack of peripheral stimulation in the ventrobasal thalamus. In addition to the spontaneous pain behavior elicited by CCI, several abnormalities occur during stimulation-induced pain, including thermal hypersensitivity and mechanical allodynia. The development of these abnormal stimulus-induced pain has also been described in areas outside the injured nerve supply, which are not supplied by injured nerves.

Behavioral tests of thermal hypersensitivity and mechanical allodynia were used to assess different components of neuropathic pain. Baseline data for each test were collected before the experiments; all animals were also tested for chronic pain behavior 13-25 days after CCI surgery, one day before vehicle administration (0.04 ml sterile water/10 g body weight) or after drug and vehicle/drug administration. The order of pain-related behavioral tests, namely (1) thermal hypersensitivity, (2) mechanical allodynia, was determined so that the effects of one would only minimally influence the other. The test procedures and results are presented separately for each aspect of chronic pain. 15 min before the first behavioral test, either 0 (vehicle, 0.04 ml/10 g body weight), or 5, 10, 20, or 40 mg/kg SPM 927 (n = 7-23/group) was administered.

(1) Thermal hypersensitivity was defined as the response to radiant heat, with the latency of withdrawal being

-27were measured when radiant heat was applied to the subplanar surface of the ligated rat hind paw according to the Hargreaves method. Compared to the baseline latency(s), the latency of paw withdrawal to thermal stimuli is significantly reduced, which can be interpreted as the development of thermal hypersensitivity following chronic compression injury.

As shown in Table 2, SPM 927 dose-dependently attenuated the thermal hypersensitivity induced by compression injury [latency time (s) ± SEM]. A significant effect was observed only at the highest doses (20 and 40 mg/kg ip), with the maximal effect occurring at 20 mg/kg ip.

Table 2

Thermal hypersensitivity, CCI model, rat

Dose mg/kg Number of animals Baseline After surgery After surgery+SPM 927 0 13 9.7+0.73 6.9±0.28 7.3±0.42 5 7 10.5+0.68 8.1+0.59 9.1±0.97 10 7 9.2+0.68 7.0±0.60 8.0±0.58 20 8 9.9±0.69 6.9±0.56 9.7+0.95* 40 8 8.3±0.57 7.4±0.47 10.2±0.77*

* = significant difference compared to vehicle (ANOVA, corrected for multiple comparisons, p < 0.05).

Mechanical sensitivity and allodynia of the ligated rat hind paw were quantified by the rapid paw withdrawal response, a response to a normally innocuous mechanical stimulus.

-28 as previously described. The ability to respond to mechanical stimuli was tested using a calibrated electronic Von Frey pressure algometer, with the data subjected to direct computer analysis. The significant post-operative reduction was compared with the baseline pressure (g/mm ² ) required to produce rapid paw withdrawal in response to mechanical stimuli, which is interpreted as mechanical allodynia.

(2) SPM 927 dose-dependently reduces the intensity of mechanical allodynia induced by unilateral nerve ligation, see Table 3 [pressure (g/mm ² ) + SEM]. Regression analysis revealed a positive linear relationship between the dose of SPM 927 and the force required to induce paw withdrawal.

Table 3

Mechanical allodynia, CC1 model, rat

Dose mg/kg Number of animals Baseline After surgery After surgery+SPM 927 0 20 41.6±2.20 18.7±2.08 20.2± 1.89 5 11 53.6±3.34 16.4+2.56 21.8+2.33 10 17 42.9±2.54 21.1±2.12 29.2+2.84* 20 8 46.0±2.62 24.6±2.78 39.5±3.62* 40 9 48.3±3.83 23.8±2.23 42.9+5.47*

= significant difference compared to vehicle (ANOVA, corrected for multiple comparisons, p < 0.05).

Example 3

Randall-Selitto paw pressure test, rat

The potential for further antinociceptive efficacy of SPM 927 was determined in an acute inflammatory rat model using the modified Randall-Selitto method. Acute inflammation was induced by subcutaneous injection of carrageenan (1.0 mg in 0.1 ml saline/paw), a nonspecific inflammatory agent; the injection was performed into the planar surface of the hind paws of the animals. Mechanical sensitivity and nociceptive thresholds were measured using an algesimeter that applied a steadily increasing mechanical force (10 mm Hg/second) to the inflamed hind paw. The mechanical nociceptive threshold was defined as the pressure (mm Hg) that caused the rat to vocalize, struggle, or withdraw its paw. Since, based on the original description, the Randall-Selitto mechanical paw pressure test is considered a standard for testing the efficacy of new compounds, we used it to measure the reduction in acute inflammatory pain.

SPM 927 or vehicle (sterile water, 0.04 ml/10 g body weight) was administered i.p. 45 min after carrageenan administration, which means that this occurred 15–20 min before behavioral testing. Compared to the threshold response of vehicle-treated controls, increasing pressure was required to elicit behavioral responses, which is considered antinociception. SPM 927 at 20 and 40 mg/kg i.p. doses significantly increased the pressure required to withdraw the paw in the Randall-Selitto paw pressure test in carrageenan-induced acute inflammation, indicating a reduction in mechanical hypersensitivity, see Table 4 [pressure (mm Hg) ± SEM, n = 12/group].

Table 4

Mechanical hyperalgesia, modified Randall-Selitto, rat

Dose mg/kg Number of animals Carrageenan itself Carrageenan + SPM 927 0 101.5238±14.9666 40.85714±9.319 45.07143+5.569 20 142.5694±12.834 108,222±10,180 164.7639±13.533* 40 164.8889±18.360 89.963±7.457 232,741±22,034*

* = significant difference compared to vehicle (ANOVA, corrected for multiple comparisons, p < 0.05).

Due to the variability of baseline responses and mechanical hypersensitivity following carrageenan injection, direct comparison of absolute paw pressures required to elicit behavioral responses is not possible. However, vehicle (0 mg/kg, sterile water, 0.04 ml/10 g body weight) has little effect on behavioral responding, whereas SPM 927 at 20 and 40 mg/kg ip significantly reduces carrageenan-induced hypersensitivity.

Test results:

Harkoseride has been shown to be an antinociceptive agent in several different experimental animal models, reflecting different types and symptoms of pain. Prolonged inflammatory nociception in the rat formalin test and mechanical allodynia in the rat CCI model indicated that these were the most sensitive to the effects of SPM 927, showing a significant dose effect in nociceptive behavioral measures, even at a dose of 10 mg/kg ip.

-31 Furthermore, higher doses of SPM 927 produced statistically significant reductions in pain in other types of nociception, thermal hypersensitivity (paw flick Hargreaves test, rat CCI model), and mechanical hypersensitivity, which occur due to acute inflammation (modified rat Randall-Selitto test).

Thus, the antinociceptive profile of SPM 927 differs from traditional analgesics, both opioids and standard anti-inflammatory drugs of the NSAID type (non-steroidal anti-inflammatory drugs), and to our surprise, the anti-nociceptive profile obtained and the data described in Figures 1-4 differ from the profiles and values of other anticonvulsants used as analgesics.

The weak but non-significant effects in thermal and mechanical hypersensitivity led to the following studies.

Example 4

Anti-nociceptive effects of harkoseride in an animal model of rheumatoid arthritis

In the next series of experiments, harkoseride will henceforth be called SPM 927.

Proceedings:

The experiments were performed on female Wistar rats, which weighed 80-90 g at the beginning of the experiments. Arthritis was induced by intraplantar injection of Freund's complete adjuvant (FCA, 0.1 ml) in the hind paw. The drugs were administered 11 days after the FCA injection, and the animals showed signs of secondary systemic arthritis. Mechanical hypersensitivity

-32 was then applied acutely and measured by the paw pressure test (Randall Selitto method), where supraspinal vocalization was considered as the biological endpoint of the nociceptive response. Measurements were made at the following time points: 0 min (before drug injection) and 15, 30, 60 min, and 24 h after drug injection, and all data were expressed as percentage of maximum possible effect (MPE %).

Ten groups of 15 rats were used, each receiving the following treatments:

Number FCA drug [dose mg/kg]/time Note 1 no no healthy controls 2 yes no arthritic controls 3 yes SPM 925(5)acute treatment group (antinociceptive effects) 4 yes SPM 925(10)acute treatment group (antinociceptive effects) 5 yes SPM 925(20)acute treatment group (antinociceptive effects) 6 yes SPM 925(30)acute treatment group (antinociceptive effects) 7 yes SPM 925(40)acute treatment group (antinociceptive effects) 8 yes SPM 925(30)early (with FCA) treatment group (anti-inflammatory effects)

9 no morphine (10) positive control group (normal conditions) 10 yes morphine (10) positive control group (diseased condition)

Results:

MPE % Group Treatment 15 minutes 30 minutes 60 minutes 24 hours 1 control -5 -2 +2 -5 2 FCA/VEH + 12 +2 0 +3 3 FCA/SPM 5 -5 -5 -12 -14 4 FCA/SPM 10 +7 -2 0 -5 5 FCA/SPM 20 + 1 -20 -9 -20 6 FCA/SPM 30 +58 +33 + 16 -8 7 FCA/SPM 40 + 100 + 100 + 14 -7 8 FCA/SPM 30 (early) -14 -7 -3 -11 9 MOR 10 + 100 + 100 + 100 +2 10 FCA/M0R10 + 100 + 100 + 100 -7

SPM 927 showed dose-dependent antinociceptive effects, but no anti-inflammatory effects were observed. Antinociceptive effects began at doses of 30 mg/kg and were most pronounced within the first 30 minutes of testing. Morphine, as a positive control, showed clearly detectable antinociceptive effects in both arthritic and normal animals.

-34Following:

Surprisingly, SPM 927 unexpectedly exhibited dose-dependent antinociceptive effects in rats with arthritis induced by Freund's complete adjuvant (significant doses: 30 and 40 mg/kg). This type of antinociception was not due to potential anti-inflammatory effects. In such a chronic inflammatory pain state, the antinociceptive effect of SPM 927 (see Figure 1) indicated full intrinsic activity, suggesting that SPM 927 is effective in the treatment of rheumatoid arthritic pain as well as secondary inflammatory osteoarthritis.

Claims (35)

-35 PATENT CLAIMS 1. Use of a compound of general formula (I), wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or substituted with at least one electron withdrawing or donating group; R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic compound, lower cycloalkyl, lower cycloalkyl lower alkyl, all of which are unsubstituted or substituted with at least one electron withdrawing or donating group; and R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic compound, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or ZY, where R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing or donating group; and where the heterocyclic group in _R2 and _R3 may be furyl, thienyl, pyrazolyl, pyrrolyl, -36imidazolyl, indolyl, thiazophil, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; Z is O, S, S(O)2, NR6', PR4 or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halogen, heterocyclic compound, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with at least one electron withdrawing or donating group; or ZY together are: NR4NR5R7, NR4OR5, ONR4R7, OPR4R7, PR4OR5, SNR4R7, NR4SR7, SPR4R5 or PR4SR7, NR4PR5R6 or PR4NR5R7, NR4C-R5, _SCR5 , NR4C-OR5, SC-OR5; II II II II 0000 R e' is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R 4 may be unsubstituted or substituted with at least one electron withdrawing or donating group; R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, where R4, Rs and Re may be unsubstituted or substituted with at least one electron withdrawing or donating group; and -37R ₇ is R ₆ or COOR s or COR s; hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, wherein R ₇ may be unsubstituted or substituted with at least one electron withdrawing or donating group; R s is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing or donating group; and n is 1-4; and a is 1-3, or pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment of pain presenting various types of acute and chronic symptoms, in particular for the treatment of non-neuropathic inflammatory pain in mammals. 2. Use of a compound according to claim 1, wherein one of R2 and R3 is hydrogen. 3. Use of a compound according to claim 1, wherein n is 1. 4. Use of a compound according to claim 1, wherein R2 and R3 are hydrogen and n is 1. 5. Use of a compound according to claim 1, wherein R is aryl lower alkyl and R1 is lower alkyl. 6. Use of a compound according to claim 1, wherein R2 and R3 are independently hydrogen, lower alkyl, or ZY; Z is O, NR4 or _PR4 ; Y is hydrogen or lower alkyl, or -38ZY _is NR5R6R, _NR5OR6 , ONR5R7, _NR5CR6 or _{NR5C - OR6} . II II o o 7. Use of a compound according to claim 4, wherein R2 and R3 are independently hydrogen, lower alkyl, or ZY; Z is O, NR4 or PR< Y is hydrogen or lower alkyl; ZY is NR ₅ R ₆ R, NR 5 OR 6 , ONR 5 R 7 , NR ₅ CR ₆ or NR 5 C-OR 6 . II II o o 8. Use of a compound according to claim 4, wherein R2 is hydrogen and R3 is lower alkyl, which may be unsubstituted with an electron withdrawing or donating group, NR4OR5, or ONR4R7. 9. Use of a compound according to claim 4, wherein R3 is lower alkyl, unsubstituted or substituted with hydroxy or lower alkoxy, NR4OR6 or ONR4R7, wherein R5 and R7 are independently hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group is unsubstituted or substituted with an electron withdrawing group, and R1 is lower alkyl. 10. Use of a compound according to claim 9, wherein aryl is phenyl. 11. Use of a compound according to claim 9, wherein aryl is phenyl and is unsubstituted or substituted with halogen. 12. Use of a compound according to claim 1, wherein the compound: -39(R)-2-acetamido-N-benzyl-3-methoxypropionamide, O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycine benzylamide; D-1,2-(N,O-Dimethylhydroxylamino)-2-acetamidoacetic acid benzylamide; D-1,2-(O-methylhydroxylamino)-2-acetamidoacetic acid benzylamide. 13. Use of a compound according to claim 1, wherein the pain is of a non-neuropathic inflammatory type. 14. Use of a compound according to claim 9, wherein the pain is of a non-neuropathic inflammatory type. 15. Use of a compound according to claim 1, wherein the pain is acute. 16. Use of a compound according to claim 1, wherein the pain is chronic. 17. Use of a compound according to claim 1, wherein the pain is of a chronic inflammatory type. 18. Use of a compound according to claim 1, wherein the pain is due to rheumatoid arthritis. 19. Use of a compound according to claim 1, wherein the pain is of the secondary inflammatory osteoarthritis type. 20. Use of a compound according to claim 1, wherein the pain is non-nociceptive. 21. Use of a compound of formula (II) wherein Ar is aryl which is unsubstituted or substituted by at least one halogen group; R ₃ is C 1-3 lower alkoxy; and R 1 is C 1-3 lower alkyl; -40 or their pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions for the treatment of pain presenting various types of acute and chronic symptoms, especially for the treatment of non-neuropathic inflammatory pain in mammals. 22. Use of a compound according to claim 21, wherein Ar is unsubstituted phenyl, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 23. Use according to claims 21 and 22, wherein the halogen group is fluoro, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 24. Use according to claims 21 and 22, wherein R3 is C1-3 alkoxy and Ar is unsubstituted phenyl, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 25. Use of a compound of formula (II) in the R configuration, wherein Ar is phenyl, unsubstituted or substituted with at least one halogen group; R3 is lower alkoxy having 1-3 carbon atoms; and R1 is methyl; or pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 26. Use of a compound according to claim 25, which is substantially enantiopure, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. -41 ₉ · · · · r . 27. Use according to claims 25 and 26, wherein Ar is unsubstituted phenyl, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 28. Use according to any one of claims 25-27, wherein the halogen group is fluoro, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 29. Use according to any one of claims 25-28, wherein R3 is C1-3 alkoxy and Ar is unsubstituted phenyl, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain. 30. Use of (R)-2-acetamido-N-benzyl-3-methoxypropionamide, or a pharmaceutically acceptable salt thereof, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain in mammals. 31. Use of (R)-2-acetamide-N-benzyl-3-methoxypropionamide, or a pharmaceutically acceptable salt thereof, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain in mammals. 32. Use of a compound according to claim 31 or a pharmaceutically acceptable salt thereof for the treatment of rheumatoid arthritis pain. 33. Use of a compound of claim 31 or a pharmaceutically acceptable salt thereof in the treatment of pain secondary to inflammatory osteoarthritis. 34. A compound according to any one of claims 30-33, which is substantially enantiopure, for the preparation of pharmaceutical compositions for the treatment of non-neuropathic inflammatory pain in mammals. -42• * e f · · • » · ·· 35. A pharmaceutical composition comprising an amount of any of the compounds of any one of claims 1-28 effective for treating non-neuropathic inflammatory pain and a pharmaceutically acceptable carrier. The authorized person is Ádám Szentpéteri H-1062 BuJapeSt; 'Mieton.· 461- iOOO Fax: 461-1099 abadalmi t Sfclmda